The ability of controlling neuronal growth and differentiation will be useful for the study of the underlying mechanisms of the nervous system, the treatment of neuronal diseases, and the effective repair of damages to nerve tissues. It has therefore been the focus of scientific research for a long time.
After years of study, it was realized that electrical stimulation can enhance neurite outgrowth in vitro and enhance nerve cell regeneration in vivo. Work by other researchers has indicated that neurite outgrowth was enhanced on the surface of piezoelectric material (Aebischer, et al., Piezoelectric guidance channels enhance regeneration in the mouse sciatic nerve after axotomy, Brain Research, 1987, 436(1), 165-168). This effect has been attributed to the presence of surface-bound charges resulting from minute mechanical stresses on the material. The exact mechanism of the observation is not yet clear. One theory is that certain proteins or other molecules that are critical to neurite extension become redistributed in the electrical field. Alternatively, these proteins could have undergone conformational changes that are favorable to neurite extension.
Conductive polymers represent a new class of materials whose electrical and optical properties can be controllably varied over a wide range, often in a reversible manner. Conductive polymers are stable, can be used in physiological cell culture media or body fluid for extended time, and have good compatibility with neurons. (C. E. Schmidt, V. R. Shastri, J. P. Vacanti, R. Langer, Stimulation of neurite outgrowth using an electrically conducting polymer, Proc. Natl. Acad. Sci. USA, 1997, 94, 8948-8953). It was also shown recently that electrical stimulation of neurons using conductive polymers as conductive media enhances neurite outgrowth. (A. Kotwal, C. E. Schmidt, Electrical stimulation alters protein adsorption and nerve cell interactions with electrically conducting biomaterials, Biomaterials, 2001, 22, 1055-1064; C. E. Schmidt, V. R. Shastri, J. P. Vacanti, R. Langer, Stimulation of neurite outgrowth using an electrically conducting polymer, Proc. Natl. Acad. Sci. USA, 1997, 94, 8948-8953). Researchers have also implanted conductive polymers as a scaffold in vivo, and used electrical stimulus to connect severed nerve tissues under the guidance of the scaffold (V. R. Shastri, C. E. Schmidt, R. S. Langer, J. P. Vacanti, U.S. Pat. No. 6,095,148, Aug. 1, 2000). Use of microelectrodes or arrays of microelectrodes to record electrophysiological signals of neurons and nerve networks has been studied since the 1970's, and tremendous progress has been made in recent years. One way is to insert multiple microelectrodes into a live subject to measure extracellular signals. The electrodes can be in the shape of spikes, with multiple electrodes being a cluster of spikes (E. Fernandez, J. M. Ferrandez, J. Ammermuller, R. A. Normann, Population coding in spike trains of simultaneously recorded retinal ganglion cells, Brain Research, 2000, 887, 222-229; D. J. Warren, E. Fernandez, R. A. Normann, High resolution two-dimensional spatial mapping of cat striate cortex using a 100-microeletrode array, Neuroscience, 2001, 105(1), 19-31; P. J. Rousche, R. S. Petersen, S. Battiston, S. Giannotta, M. E. Diamond, Examination of the spatial and temporal distribution of sensory cortical activity using a 100-electrode array, Journal of Neuroscience Methods, 1999, 90, 57-66), or can be positioned in a cone, with each electrode being a planar electrode on the bottom surface of the cone (G. Ensell, D. J. Banks, P. R. Richards, W. Balachandran, D. J. Ewins, Silicon-based microelectrodes for neurophysiology, micromachined form silicon-on-insulator wafers, Medical & Biological Engineering & Computing, 2000, 38, 175-179); another method is to use a two-dimensional array of microelectrodes to simultaneously measure multiple measured cells cultured in vitro (Y. Jimbo, A. Kawana, P. Parodi, V. Torre, The dynamics of a neuronal culture of dissociated cortical neurons of neonatal rats, Biological Cybernetics, 2000, 83, 1-20; T. Tateno, Y. Jimbo, Activity-dependent enhancement in the reliability of correlated spike timings in cultured cortical neurons, Biological Cybernetics, 1999, 80, 45-55; M. P. Maher, J. Pine, J. Wright, Y. C. Tai, The neurochip: a new multielectrode device for stimulating and recording from cultured neuron, Journal of Neuroscience Methods, 1999, 87, 45-56); the third method is to make spikes containing the microelectrode arrays of the second method along with embryonic neurons, insert the spikes into a live subject, and observe the integration and communication of signals between cells on the microelectrode array and cells in the subject. (J. Pine, M. Maher, S. Potter, Y. C. Tai, S, Tatic-Lucic, J. Wright, A cultured neuron probe, Proceedings of IEEE-EMBS Annual Meeting, Amersterdam, the Netherlands, 1996, November, paper #421). The advantage of measuring signals in vitro is that one can control the positioning of the cell and the condition of the cell culture, thereby studying various functions of the neurons clearly and conveniently. However, the direction of neurite outgrowth is usually random and hard to control, which makes it difficult to establish a nerve network for the purpose of recording the communication of electrophysiological signals. It also makes it difficult for implanted neurons to integrate into the nervous system of the subject and communicate with the nervous system. Some researchers have mechanically forced neurons to grow only in defined channels. This kind of mechanical restriction, however, affects the normal outgrowth of neurites. Other researchers have used patterns formed by materials such as metal oxide to study the guidance of these materials on neurites (Yashihiko Jimbo, P. C. Robinson, Akio Kawana, Simultaneous Measurement of Intracellular Calcium and Electrical Activity from Patterned Neural Networks in Culture, IEEE transaction on biomedical engineering, 1993, 40(8), 804-810).